The efficacy of adjunctive alpha-blockers on ureteroscopy procedure for ureteral stones: a systematic review and meta-analysis [version 2; peer review: 2 approved]

Background: Urolithiasis cases are a common condition, and the number is still growing today. The prevalence of urinary tract stones globally currently ranges from 2-20% with a recurrence rate of around 50%. The present study aims to investigate the efficacy of adjunctive alpha-blockers in improving the success rate of ureteroscopy (URS) procedure for urolithiasis. Methods: We reviewed articles obtained from MEDLINE, CENTRAL, CINAHL, and Elsevier from 14 August to 9 September 2020, comparing alpha-blockers as adjunctive therapy, versus either a placebo or no drug at all, in post-URS urolithiasis patients. There were no restrictions on the type of URS and alpha-blockers given to patients. The quality of studies included was assessed using Cochrane’s Risk of Bias Assessment for Randomized-Controlled Trials. Results: Forest plot analysis emphasizes the statistically significant difference among the group, where the adjunctive alpha-blocker group had pooled relative risk (RR) of being stone-free, readmitted due to initial URS failure, having an overall complication, having haematuria, getting their ureteral mucous injured, and suffering a colic episode was 1.71 (95% CI, 1.11–1.24), 0.50 (95% CI, 0.25–1.01), 0.41 (95% CI, 0.27–0.61), 0.42 (95% CI, 0.22–0.79), 0.31 (95% CI, 0.13–0.73), and 0.21 (95% CI, 0.06–0.69), respectively. Conclusions: Alpha blockers minimize the frequency and duration of ureteral contractions, allowing smooth stone expulsion. With this knowledge, it is expected to help clinicians decide the importance of adjunctive alpha-blocker administration.


Introduction
In the last decade, urolithiasis has become a common condition, and the number continues to increase. The prevalence of urinary tract stones globally currently ranges from 2-20% with a recurrence rate of around 50%. The increase in urinary tract stones incidence was also followed by the rise in the frequency of urinary tract endoscopy, one of which was retrograde or antegrade ureterorenoscopy, which was indicated to treat ureteral stones and kidney stones 1 . Compared to the extra-corporeal shock-wave lithotripsy (ESWL) procedure, (URS) is more preferred, as it has been proven to achieve higher success rates in a single operation 2,3 .
In recent literature, the adjunctive alpha-blocker is recommended to facilitate distal ureteric stone expulsion, decrease postoperative complications, improve stents tolerability, and reduce colic episodes to reduce the necessity for secondary procedure retreatment 1 .
The present study aims to investigate the efficacy of adjunctive alpha-blockers for improving the success rate of the URS procedure for urolithiasis. By conducting this review and analysis, a definite conclusion regarding the effectiveness can be achieved. Thus, clinicians can decide the necessity of adjunctive alpha-blockers.

Description of condition
This review was done according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statements 4 . This study attempted to improve alpha-blocker therapy effectiveness in post-URS urolithiasis patients, with success rate parameters. Thus, this meta-analysis included studies which compared alpha-blockers as adjunctive therapy, versus either a placebo or no drug at all, in post-URS patients. No restrictions on the type of URS were performed in patients. There were also no restrictions on the kind of alpha-blocker given to patients. The success rate was then defined as the stone-free rate and overall postoperative complication rate.

Database searching and literature screening
We performed an article search on four electronic databases (MEDLINE/Pubmed, CENTRAL/Cochrane, CINAHL/EBSCO-Host, and EMBASE/Elsevier). The investigation was carried out from 14 August to 9 September 2020. PICOS were used to trace studies and identify the suitability of any we found 5 . We used specific keywords, adjusted to each search engine specification, in the form of (postoperative OR adjunctive) AND (alpha-blocker OR tamsulosin OR alpha-adrenergic antagonists OR Alpha-adrenoreceptor antagonists OR doxazosin OR terazosin OR alfuzosin OR prazosin) AND (ureteroscopy OR URS OR ureterorenoscopy OR retrograde intrarenal surgery) AND ureteral stone. We also looked at a reference list of several reviews to expand the search coverage of the study.

Study selection
Study selection was carried out independently and duplicated by each author, referring to inclusion and exclusion criteria. The inclusion criteria in this study included: 1) RCT or quasi-RCT studies that were compatible with PICOS; 2) English/Indonesian written articles; 3) Full-text articles available; 4) The output assessed were, at least, one of postoperative stone-free rate or overall complication rate; and 5) Published between 1 January 2000 and 31 December 2020.
There were no restrictions on the type of URS and alpha-blockers given to patients. The exclusion criteria for this study included review articles, case reports, case series, editorial letters, studies on animals, and/or studies in the process of peer review (has not been published yet).
The decision to study eligibility was determined by each author independently. Any disagreement was resolved by discussion.

Data extraction and outcome of interest
Data extraction was carried out by each author independently and in duplication. We extracted the study's primary characteristics, including the first author, location, sample size, and publication year.
Following the dependent variables in this meta-analysis, we also extracted patient baseline data and postoperative data, including a stone-free rate and overall complication rate. We also noted the type of alpha-blocker and the duration of alpha-blocker administration.
This study explored the efficacy of adjunctive alpha-blockers in increasing URS's success rate in urolithiasis patients, divided into the stone-free rate and overall complication rate, in the form of relative risk (RR). We used a 2×2 contingency table to obtain each study's RRs and pooled the overall RRs using the Review Manager 5.3 application 6 . Analysis using the DerSimonian and Laird random-effects model was performed when high heterogeneity was found.

Study quality assessment
To see the precision and examine publication bias, this meta-analysis utilized funnel plots, which were also produced via Review Manager 5.3 6 .

Literature findings
We searched five electronic databases, using specific keywords tailored to each database, to improve search sensitivity and specificity. The total records retrieved were 520 studies, and 131 studies were then excluded as there were duplications.

Amendments from Version 1
The new version clarifies that alpha-blockers exert their effects on the distal part of the ureter muscle. Due to the fact that kidney and bladder stones can form in a number of sites, the author and reviewer felt it was critical to express this openly. The author expects that by defining the location of efficacy for alpha-blockers, which was the distal ureter, this study may make future implementation easier.

REVISED
From 389 studies screened, 376 studies were further excluded because of unrelated topics and objectives, resulting in 13 studies to be assessed for eligibility. Another five studies were later excluded due to unsuitable study design (n = 2) and review articles (n = 3). We obtained eight studies that were included in the qualitative and quantitative synthesis. The summary of study identification and selection according to the PRISMA Statement flow diagram are shown in Figure 1 and Table 1.

Study characteristics
Three of the eight studies we included in this study were multicenter, prospective, randomized trials 7-9 . While the other five were a single-center, prospective, randomized trial 1,3,10,11 . However, the numbers of patients enrolled in the pilot studies did not differ significantly between studies. Overall, the total number of patients included in this meta-analysis was 913 patients.
Seven of the eight studies gave alpha-blockers before URS, three of those gave Tamsulosin 0.4 mg once daily for seven days before surgery 1,8,10 . Two studies administered alpha-blockers only once, the day before surgery 3,9 . One study gave Silodosin 8 mg once daily for ten days before surgery 10 , and one other study gave Tamsulosin 0.4 mg once daily for 14 days  Table 2.

Summary of bias risk
Of the eight studies included in this meta-analysis, five had a high risk of bias because assessor outcome blinding was not performed. One study clearly stated no blinding in patients who were given intervention or control 11 . Selection bias in some studies was also considered high, because no allocation concealment was performed. In general, the quality of the studies included in this meta-analysis varied from low to high.
The bias assessment was carried out independently by each author and in duplication, in which all authors assessed all articles. Disagreements between the authors were resolved by discussion or consensus. Figure 2 visualizes the summary of bias risk.

Stone-free rate
The stone-free rate was found to be higher in patients given adjunctive alpha-blockers in most of the studies. A study by Aydin et al. 2017 9 , found no difference at all in the stone-free rates of patients with and without adjunctive alpha-blockers one day before URS surgery. However, this study also compared alpha-blocker administration three days before surgery with a placebo and found a significant difference between the placebo and alpha-blocker groups.
Based on the results of the meta-analysis in Figure 3, it could be seen that the pooled RR favors the experimental group (adjunctive alpha-blocker), with a value of 1.17 (95% CI, 1.11-1.24). This indicates that a significantly higher stone-free rate was found in the adjunctive alpha-blocker patient.

Overall complication rate
In all studies, the complication rate was higher in the control group, either general complication or overall complication, hematuria, or mucosal injury. The alpha-blockers group had a significantly lower risk of complications than the placebo group, with a pooled RR of 0.41 (95% CI, 0.27-0.61). In this meta-analysis, the heterogeneity was recorded at only 0%; thus, we used a fixed-effect model to pool the effect estimate.
injury, and colic episode. For each of these complications, the alpha-blocker group was shown to have a lower risk of developing these complications. For all three types of complications, the alpha-blocker group had a significantly lower risk, with the pooled RR for hematuria, mucosal injury, and a colic episode of 0.42 (95% CI, 0.22-0.79), 0.31 (95% CI, 0.13-0.73), and 0.21 (95% CI, 0.06-0.69), respectively. These are summarized in Figure 4.

Discussion
According to this systematic review and meta-analysis, postoperative alpha-blocker is associated with URS procedure's success rate for urolithiasis 2,13 . From the forest plot, it was discovered that patients having postoperative alpha-blockers are more likely to be stone-free with the RR=1.17 (95% CI, 1.11-1.24). This means that patients consuming postoperative alpha-blockers are 1.17 times more likely to be stone-free. The risk ratio ranges from 1.11-1.24, which are both greater than 1. Thus, it can be concluded that postoperative alpha-blocker is effective in increasing the stone-free rate after ureteroscopy. Tamsulosin, an alpha-1A blocker, has been shown to improve the distal ureteral stone expulsion rate and minimize the probability of colic episodes in patients during watchful waiting 15,16 . It relaxes the muscle of the distal ureteral wall, aiding gravel clearance after URS or ESWL procedure. Furthermore, a relaxed ureter allows the instrument forwarding to become easier. In patients with Tamsulosin, the ureteral orifices were dilated, easily identified, and provided a more accessible entrance for the ureteroscope 8,17 . Tamsulosin also lessens the amplitude of ureteral contractions and shortens the duration between contractions 15,18 .
Postoperative complications outcome is also affected by the administration of postoperative alpha-blockers 19,20 . It was found that endoscopic treatments without the administration of adjunctive alpha-blockers are associated with a higher probability   This systematic review and meta-analysis have several strengths. Firstly, this systematic review and meta-analysis included a relatively broad scope of population. This review then assesses the primary outcome and considers other additional outcomes, which is also essential in clinical practices, albeit not widely studied. Low risk of bias in included studies, utilization of guidelines, no heterogeneity between studies, symmetrical funnel plots as shown in Figure 5, and high specificity also strengthen this study.

Conclusions
In conclusion, our study shows that the administration of adjunctive alpha-blockers improves the URS procedure's success rate for ureteral calculi in terms of increasing stone-free rate, reducing postoperative complications, and minimizing colic episodes. This is because the alpha-blocker relaxes and reduces the ureteral wall's contractions, allowing easier stone clearance. Alpha-blockers have been shown to enhance the rate of distal ureteral stone ejection. The use of -blockers in Figure 5. Funnel plots of stone-free rate (A), overall complication rate (B), hematuria (C), mucosal injury (D), readmission rate (E) and colic episodes (F). Aside from the strengths, this systematic review and meta-analysis has a limitation. This study's limitation is that there were only eight studies eligible for review, and there were only two studies for each outcome, which makes its representability somewhat questionable.
the conservative therapy of distal ureteral stones is advised in the appropriate clinical context.

Data availability
Open Science Framework: PRISMA checklist and flow chart for 'The efficacy of adjunctive alpha-blocker on ureteroscopy procedure for ureteral stones: a systematic review/meta-analysis'